The field of the present invention relates to the delivery of energy impulses (and/or fields) to bodily tissues for prophylactic purposes. It relates more specifically to the use of non-invasive devices and methods for transcutaneous electrical nerve stimulation and magnetic nerve stimulation, along with methods for averting imminent medical disorders using energy that is delivered by such devices. The disorders comprise the following medical problems: asthma attacks and COPD exacerbations, epileptic seizures, migraine or other headaches having sudden onset, ventricular fibrillation/tachycardia, myocardial infarction, transient ischemic attacks or strokes, atrial fibrillation, panic attacks and attacks of depression. According to the invention, a patient at risk for such attacks is monitored, preferably using ambulatory or noninvasive sensors; signals from the sensors are analyzed automatically using a device to forecast that an attack may be imminent; the analyzing device warns the patient or health provider that an attack may be imminent; and transcutaneous electrical nerve stimulation or magnetic nerve stimulation, preferably of the vagus nerve, is performed is order to avert, prevent, delay, abort, shorten, or ameliorate the attack.
The use of electrical stimulation for treatment of medical conditions has been well known in the art for nearly two thousand years. It has been recognized that electrical stimulation of the brain and/or the peripheral nervous system and/or direct stimulation of the malfunctioning tissue holds significant promise for the treatment of many ailments, because such stimulation is generally a wholly reversible and non-destructive treatment.
One of the most successful applications of modern understanding of the electrophysiological relationship between muscle and nerves is the cardiac pacemaker. Although origins of the cardiac pacemaker extend back into the 1800's, it was not until 1950 that the first practical, albeit external and bulky, pacemaker was developed. The first truly functional, wearable pacemaker appeared in 1957, and in 1960, the first fully implantable pacemaker was developed.
Around this time, it was also found that electrical leads could be connected to the heart through veins, which eliminated the need to open the chest cavity and attach the lead to the heart wall. In 1975 the introduction of the lithium-iodide battery prolonged the battery life of a pacemaker from a few months to more than a decade. The modern pacemaker can treat a variety of different signaling pathologies in the cardiac muscle, and can serve as a defibrillator as well (see U.S. Pat. No. 6,738,667 to DENO, et al., the disclosure of which is incorporated herein by reference).
Another application of electrical stimulation of nerves has been the treatment of radiating pain in the lower extremities by stimulating the sacral nerve roots at the bottom of the spinal cord (see U.S. Pat. No. 6,871,099 to WHITEHURST, et al., the disclosure of which is incorporated herein by reference).
Many such therapeutic applications of electrical stimulation involve the surgical implantation of electrodes within a patient. In contrast, devices used for the medical procedures that are disclosed here stimulate nerves by transmitting energy to nerves and tissue non-invasively. They may offer the patient an alternative that does not involve surgery. A medical procedure is defined as being non-invasive when no break in the skin (or other surface of the body, such as a wound bed) is created through use of the method, and when there is no contact with an internal body cavity beyond a body orifice (e.g., beyond the mouth or beyond the external auditory meatus of the ear). Such non-invasive procedures are distinguished from invasive procedures (including minimally invasive procedures) in that invasive procedures do involve inserting a substance or device into or through the skin or into an internal body cavity beyond a body orifice. For example, transcutaneous electrical nerve stimulation (TENS) is non-invasive because it involves attaching electrodes to the surface of the skin (or using a form-fitting conductive garment) without breaking the skin. In contrast, percutaneous electrical stimulation of a nerve is minimally invasive because it involves the introduction of an electrode under the skin, via needle-puncture of the skin (see commonly assigned co-pending US Patent Application 2010/0241188, entitled Percutaneous Electrical Treatment of Tissue to ERRICO et al, which is hereby incorporated by reference in its entirety).
Potential advantages of non-invasive medical methods and devices relative to comparable invasive procedures are as follows. The patient may be more psychologically prepared to experience a procedure that is non-invasive and may therefore be more cooperative, resulting in a better outcome. Non-invasive procedures may avoid damage of biological tissues, such as that due to bleeding, infection, skin or internal organ injury, blood vessel injury, and vein or lung blood clotting. Non-invasive procedures generally present fewer problems with biocompatibility. In cases involving the attachment of electrodes, non-invasive methods have less of a tendency for breakage of leads, and the electrodes can be easily repositioned if necessary. Non-invasive methods are sometimes painless or only minimally painful and may be performed without the need for even local anesthesia. Less training may be required for use of non-invasive procedures by medical professionals. In view of the reduced risk ordinarily associated with non-invasive procedures, some such procedures may be suitable for use by the patient or family members at home or by first-responders at home or at a workplace, and the cost of non-invasive procedures may be reduced relative to comparable invasive procedures.
Non-invasive transcutaneous electrical nerve stimulation (TENS) electrodes were developed originally for treating different types of pain, including pain in a joint or lower back, cancer pain, post-operative pain, post-traumatic pain, and pain associated with labor and delivery. As TENS was being developed to treat pain, non-invasive electrical stimulation using surface electrodes was simultaneously developed for additional therapeutic or diagnostic purposes, which are known collectively as electrotherapy. Neuromuscular electrical stimulation (NMES) stimulates normally innervated muscle in an effort to augment strength and endurance of normal (e.g., athletic) or damaged (e.g., spastic) muscle. Functional electrical stimulation (FES) is used to activate nerves innervating muscle affected by paralysis resulting from spinal cord injury, head injury, stroke and other neurological disorders, or muscle affected by foot drop and gait disorders. FES is also used to stimulate muscle as an orthotic substitute, e.g., replace a brace or support in scoliosis management. Another application of surface electrical stimulation is chest-to-back stimulation of tissue, such as emergency defibrillation and cardiac pacing. Surface electrical stimulation has also been used to repair tissue, by increasing circulation through vasodilation, by controlling edema, by healing wounds, and by inducing bone growth. Surface electrical stimulation is also used for iontophoresis, in which electrical currents drive electrically charged drugs or other ions into the skin, usually to treat inflammation and pain, arthritis, wounds or scars.
Stimulation with surface electrodes is also used to evoke a response for diagnostic purposes, for example in peripheral nerve stimulation (PNS) that evaluates the ability of motor and sensory nerves to conduct and produce reflexes. Surface electrical stimulation is also used in electroconvulsive therapy to treat psychiatric disorders; electroanesthesia, for example, to prevent pain from dental procedures; and electrotactile speech processing to convert sound into tactile sensation for the hearing impaired. All of the above-mentioned applications of surface electrode stimulation are intended not to damage the patient, but if higher currents are used with special electrodes, electrosurgery may be performed as a means to cut, coagulate, desiccate, or fulgurate tissue [Mark R. PRAUSNITZ. The effects of electric current applied to skin: A review for transdermal drug delivery. Advanced Drug Delivery Reviews 18 (1996) 395-425].
Another form of non-invasive electrical stimulation is magnetic stimulation. It involves the induction, by a time-varying magnetic field, of electrical fields and current within tissue, in accordance with Faraday's law of induction. Magnetic stimulation is non-invasive because the magnetic field is produced by passing a time-varying current through a coil positioned outside the body, inducing at a distance an electric field and electric current within electrically-conducting bodily tissue. The electrical circuits for magnetic stimulators are generally complex and expensive and use a high current impulse generator that may produce discharge currents of 5,000 amps or more, which is passed through the stimulator coil to produce a magnetic pulse. The principles of electrical nerve stimulation using a magnetic stimulator, along with descriptions of medical applications of magnetic stimulation, are reviewed in: Chris HOVEY and Reza Jalinous, The Guide to Magnetic Stimulation, The Magstim Company Ltd, Spring Gardens, Whitland, Carmarthenshire, SA34 0HR, United Kingdom, 2006.
Despite its attractiveness, non-invasive electrical stimulation of a nerve is not always possible or practical. This is primarily because the stimulators may not be able to stimulate a deep nerve selectively or without producing excessive pain, because the stimulation may unintentionally stimulate nerves other than the nerve of interest, including nerves that cause pain. For this reason, forms of electrical stimulation other than TENS may be best suited for the treatment of particular types of pain [Paul F. WHITE, shitong Li and Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic Pain Management. Anesth Analg 92(2001):505-13]. Accordingly, there remains a long-felt but unsolved need to stimulate nerves totally non-invasively, selectively, and essentially without producing pain.
As compared with what would be experienced by a patient undergoing non-invasive stimulation with conventional TENS or magnetic stimulation methods, the stimulators disclosed herein and in the related applications cited in the section CROSS REFERENCE TO RELATED APPLICATIONS produce relatively little pain for a given depth of stimulus penetration, but nevertheless stimulate the target nerve to achieve therapeutic results. Or conversely, for a given amount of pain or discomfort on the part of the patient (e.g., the threshold at which such discomfort or pain begins), the stimulators disclosed herein and in the related applications achieve a greater depth of penetration or power of the stimulus under the skin. When some nerves are stimulated electrically, they may produce undesirable responses in addition to the therapeutic effect that is intended. For example, the stimulated nerves may produce unwanted muscle twitches. The stimulators disclosed herein and in the related applications selectively produce only the intended therapeutic effect when they are used to stimulate the target nerve.
The stimulators disclosed herein and in those related applications are particularly useful for performing noninvasive stimulation of the vagus nerve in the neck. Invasive vagus nerve stimulation (VNS, also known as vagal nerve stimulation) was developed initially for the treatment of partial onset epilepsy and was subsequently developed for the treatment of depression and other disorders. The left vagus nerve is ordinarily stimulated at a location within the neck by first surgically implanting an electrode there, then connecting the electrode to an electrical stimulator [Patent numbers U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis, to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulation techniques for treatment of epileptic seizures, to OSORIO et al and U.S. Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders by nerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation and transcranial stimulation: An overview of stimulation parameters and neurotransmitter release. Neuroscience and Biobehavioral Reviews 33 (2009) 1042-1060; GROVES D A, Brown V. I. Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev (2005) 29:493-500; Reese TERRY, Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsy strives to improve efficacy and expand applications. Conf Proc IEEE Eng Med Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nerve stimulation: current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4]. An advantage of devices according to the present invention, which are also disclosed the related applications cited in the section CROSS REFERENCE TO RELATED APPLICATIONS, is that they can be used to perform VNS noninvasively on the neck without causing pain or nonselective nerve stimulation. Furthermore, devices disclosed in the related applications can be used to stimulate the vagus nerve at locations other than the neck.
Vagus nerve stimulation has heretofore been used to treat patients who are only at a statistical risk for experiencing epileptic seizures. For example, the patient will have been diagnosed with epilepsy or is otherwise considered to be at risk for having seizures, using statistical or epidemiological risk assessment methods. Such risk assessment methods predict only the probability of a seizure over a period of typically weeks or months, but do not attempt to forecast that an attack is imminent within a matter of minutes or other short period of time. Thus, currently practiced VNS treatment methods stimulate the patient chronically or at scheduled times, rather than stimulating at times based on predicted epileptic seizures.
It would be preferable to actually forecast an epileptic seizure so as to perform a prophylactic countermeasure, and methods have been proposed to do so [MORMANN F, Andrzejak R G, Eiger C E, Lehnertz K. Seizure prediction: the long and winding road. Brain 130(Pt 2, 2007):314-33]. Proposed countermeasures are the on-demand excretion of fast-acting anticonvulsant substances, local cooling, biofeedback operant conditioning, and electrical or other stimulation to reset brain dynamics to a state that will not develop into a seizure. The electrical stimulation countermeasures that have been proposed involved deep-brain stimulation or other uses of implanted electrodes, but not non-invasive vagal nerve stimulation. In one aspect of the present invention, non-invasive vagal nerve stimulation is performed as a countermeasure for forecasted epileptic seizure, instead of using implanted electrodes or brain stimulation.
The literature on “acute risk factors” for acute events other than epileptic seizures does not attempt to forecast and take prophylactic nerve stimulation countermeasures against the actual onset of the disease event. Instead, the goal has been detection of the attack in its early stages (e.g, transient ischemia, thrombosis, and initial signs of ventricular fibrillation, in the case of cardiovascular events [Tofler G H, Muller J E. Triggering of acute cardiovascular disease and potential preventive strategies. Circulation. 114(17, 2006):1863-72]). The treatment methods that are currently practiced in connection with such acute events are therefore generally intended only to lessen the probability that an acute event will occur over a period of weeks or months, or possibly to abort an attack that is already in progress, but not to predict and avert an attack is that is imminent within a matter of minutes or other short period of time. In one aspect of the present invention, forecasting and non-invasive vagal nerve stimulation is performed as a countermeasure for many types of acute events, comprising: asthma attacks, epileptic seizures, migraine or other headaches having sudden onset, ventricular fibrillation/tachycardia, myocardial infarction, transient ischemic attacks or strokes, atrial fibrillation, panic attacks or attacks of depression. Thus, the present invention differs from the prior art in that it attempts to forecast such an imminent attack (generally within seconds to hours), warn the patient that an attack may be imminent, and use noninvasive nerve stimulation to prevent or avert the attack.
The forecast that an attack may be imminent is based upon the automatic analysis of physiological and/or environmental signals that are provided preferably by non-invasive sensors situated on, about, or near the patient. Such sensors may comprise those used in conventional Holter and bedside monitoring applications, for monitoring heart rate, ECG, respiration, core temperature, hydration, blood pressure, brain function, oxygenation, and skin temperature. The sensors may also be embedded in garments or placed in sports wristwatches, as currently used in programs that monitor the physiological status of soldiers [G. A. Shaw, A. M. Siegel, G. Zogbi, and T. P. Opar. Warfighter physiological and environmental monitoring: a study for the U.S. Army Research Institute in Environmental Medicine and the Soldier Systems Center. MIT Lincoln Laboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141]. More sophisticated versions of conventional ambulatory monitoring devices may also be used, for example, when electrical impedance measurements are used noninvasively to image the lung, heart, or brain [David Holder. Electrical impedance tomography: methods, history, and applications. Institute of Physics Publishing, Bristol and Philadelphia; 2005].
Sensors may be selected according to their relevance to the physiology of the disease that is being forecast. For example, for some applications the sensors may measure bodily chemicals using non-invasive transdermal reverse iontophoresis [Leboulanger B, Guy R H, Delgado-Charro M B. Reverse iontophoresis for non-invasive transdermal monitoring. Physiol Meas. 25(3, 2004):R35-50]. For brain monitoring, they may comprise ambulatory EEG sensors [Casson A, Yates D, Smith S, Duncan 1, Rodriguez-Villegas E. Wearable electroencephalography. What is it, why is it needed, and what does it entail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56] or optical topography systems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M, Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearable optical topography system for mapping the prefrontal cortex activation. Rev Sci Instrum. 2009 April; 80(4):043704].
The sensors may also comprise accelerometers for detailed measurement of the patients' movements and metabolically-relevant activity [Mathie M J, Coster A C, Lovell N H, Celler B G. Accelerometry: providing an integrated, practical method for long-term, ambulatory monitoring of human movement. Physiol Meas. 2004 April; 25(2):R1-20] or for evaluation of potential motion artifacts in other signals such as the EEG [Sweeney K T, Leamy D J, Ward T E, McLoone S. Intelligent artifact classification for ambulatory physiological signals. Conf Proc IEEE Eng Med Biol Soc. 2010; 2010:6349-52]. Nearby sensors for environmental variables may also be useful for making forecasts, the values of which may be transmitted, directly in the case of ambulatory monitors or wirelessly in the case of non-portable sensors, to the device that is aggregating the signals used to make the forecast. For example, vest-based sensors would be useful for the evaluation of potential environmental asthma triggers [e.g., Kirk J. Englehardt and John Toon. Asthma attack: Vest-based sensors monitor environmental exposure to help understand causes: web page (www) at the Georgia Tech Research Institute (.gtri) of Georgia Tech (.gatech) educational domain (.edu) in subdomain: /casestudy/asthma-vest-helps-id-asthma-causes; patent application US20110144515 Systems and methods for providing environmental monitoring, to Bayer et al.; and patent U.S. Pat. No. 7,119,900; entitled Pollen sensor and method, to Okumura et al].
A common feature of asthma attacks, epileptic seizures, migraine or other headaches having sudden onset, ventricular fibrillation/tachycardia, myocardial infarction, transient ischemic attacks or strokes, atrial fibrillation, panic attacks, attacks of depression, and the like, is that they all may occur suddenly. On one level, they all have different particular mechanisms, but on a more general level they all appear to be types of phase transitions, wherein there is an abrupt change from a possibly normal physiological dynamic phase to a pathological dynamical phase. As a type of phase transition, they share features with non-biological, non-equilibrium phase transitions such as the onset of lasing in a laser or the abrupt change from laminar to turbulent flow in fluid dynamics. Such phase transitions are described by non-linear dynamical equations that exhibit generic properties immediately before the change of phase occurs [Scheffer M, Bascompte J, Brock W A, Brovkin V, Carpenter S R, Dakos V, Held H, van Nes E H, Rietkerk M, Sugihara G. Early-warning signals for critical transitions. Nature 461(7260, 2009):53-9; Christian Kuehn. A mathematical framework for critical transitions: normal forms, variance and applications. arXiv:1101.2908v1 math.DS]. Therefore, it may be generally possible to predict the imminence of pathological phase transitions such as the pathological attacks indicated above, using nonlinear as well as ad hoc analyses of relevant noninvasive ambulatory signals, obtained using ambulatory sensors such as those described in the previous paragraphs.
For many pathological attacks or transitions, it is known that vagal nerve stimulation is protective. Therefore, a patient who is promptly forewarned by the invention that such a pathological dynamical event is imminent may use noninvasive vagus nerve stimulation as a prophylactic countermeasure, with little risk of pain or adverse consequences, and with potentially much to gain by averting the onset or episode of the disease. According to the present invention, the prophylactic stimulation will ordinarily be performed in “open-loop” mode, wherein the sensors do not provide immediate feedback to determine the parameters of the stimulation (frequency, pulse width, number of pulses per burst, etc.). However, also according to the present invention, preliminary stimulations may be performed in “closed-loop” mode, wherein the sensors do provide feedback, in order to select the stimulation parameters that will eventually be used during the open-loop prophylactic stimulation. If preliminary parameter selection has not yet taken place, the prophylactic stimulation may also be performed in “closed-loop” feedback mode. Because the goal of the devices is to forecast an imminent event, feedforward methods are generally used in any case. Although the preferred stimulation methods are noninvasive, it is understood that invasive stimulation and data acquisition methods may also be used for a patient in whom electrodes have already been implanted. It is also understood that the noninvasive vagal nerve stimulation countermeasure may be used in conjunction with other countermeasures (e.g., inhaler or EpiPen for bronchoconstriction).